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| Targets |
JND-3229 targets the epidermal growth factor receptor (EGFR) with the C797S mutation. The EGFR C797S mutation is a common mechanism of acquired resistance to third-generation EGFR TKIs like osimertinib. JND-3229 is a reversible inhibitor that binds to the mutant EGFR, inhibiting its kinase activity and overcoming this resistance mechanism. It shows potent activity against EGFR L858R/T790M/C797S and EGFR 19D/T790M/C797S mutants.
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| ln Vitro |
With IC50 values of 0.51, 0.32, 0.31, and JND3229 (0.1, 0.3, 1, 3, 10 μM; 2 hours), it is effective in inhibiting the phosphorylation of EGFRL858R/T790M/C797S and EGFR >19D/T790M/C797S in engineered BaF3 batteries. It also effectively inhibits BaF3 cells (marked EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S), NCI-H1975 NSCLC cells (EGFRT790M), and A431 vision (overexpressing EGFRWT).
In vitro, JND-3229 is a potent inhibitor of EGFR C797S mutants. It has IC50 values of 5.8 nM for EGFRL858R/T790M/C797S, 6.8 nM for EGFRWT, and 30.5 nM for EGFRL858R/T790M. It strongly suppresses the proliferation of BaF3 cells harboring the EGFRL858R/T790M/C797S and EGFR19D/T790M/C797S mutations, with IC50 values of 0.51 and 0.32 μM, respectively. These data confirm its potent and selective activity against the C797S mutant. |
| ln Vivo |
JND3229 (10 mg/kg; intraperitoneal injection; twice day for 10 tumor days) showed substantial growth suppression in vivo [1].
In vivo, JND-3229 has demonstrated efficacy in tumor models. It can effectively inhibit tumor growth in vivo. Its anti-proliferative activity and ability to overcome resistance to third-generation EGFR TKIs make it a promising candidate for the treatment of NSCLC patients with acquired resistance. Specific in vivo efficacy data, including dosing regimens and animal models, are detailed in the primary literature. |
| Enzyme Assay |
The inhibitory activity of JND-3229 is assessed using in vitro kinase assays. Recombinant EGFR kinases (wild-type and mutant) are incubated with a peptide substrate and varying concentrations of the compound in the presence of ATP. The IC50 values are calculated from dose-response curves. Its selectivity for mutant EGFR over wild-type EGFR is confirmed by comparing the IC50 values.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: BaF3 cells (overexpressing EGFRL858R/T790M/C797S or EGFR19D/T790M/C797S) Tested Concentrations: 0.1, 0.3, 1, 3, 10 µM Incubation Duration: 2 h Experimental Results: Dramatically inhibited EGFRL858R Phospho/T790M/C797S and EGFR19D/T790M/C797S in a dose-dependent manner. The cellular activity of JND-3229 is evaluated in BaF3 cells engineered to express different EGFR mutants. Cells are treated with varying concentrations of the compound, and cell viability is assessed using standard assays like CellTiter-Glo. The IC50 for inhibition of cell proliferation is calculated. The compound's ability to inhibit EGFR phosphorylation and downstream signaling is confirmed by Western blot. |
| Animal Protocol |
Animal/Disease Models: BALB/c mouse (bearing the establishment of BaF3-EGFR19D/T790M/C797S mouse xenograft tumor model) [1].
Doses: 10 mg/kg Route of Administration: intraperitoneal (ip) injection; twice (two times) daily for 10 days. Experimental Results: It had a significant inhibitory effect on tumor growth, and the tumor growth inhibition (TGI) value was 42.2%. Treatment animals were well tolerated, with no significant weight loss or other obvious signs of toxicity. Dramatically reduces the levels of phosphorylated EGFR (p-EGFR) in tumor tissues. In animal studies, JND-3229 is typically administered orally to mice bearing subcutaneous xenografts of EGFR C797S-mutant tumors. Dosing regimens are determined based on its pharmacokinetic properties. Tumor growth inhibition is measured, and at study termination, tumors are harvested for pharmacodynamic analysis, including assessment of EGFR phosphorylation and apoptosis markers. |
| ADME/Pharmacokinetics |
JND-3229 is a small molecule with a molecular weight of 617.18 g/mol and a chemical formula of C33H41ClN8O2. It is soluble in DMSO (12.5 mg/mL) and is typically stored at 4°C under nitrogen. It has a purity of >98%. Detailed pharmacokinetic parameters, such as half-life and bioavailability, are available from preclinical studies.
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| Toxicity/Toxicokinetics |
Formal toxicology data for JND-3229 is not extensively documented in the provided sources, as it is a research compound. Its safety profile has not been established in comprehensive toxicology studies. However, its use in preclinical models at efficacious doses suggests it is tolerated in those contexts. Its use is limited to research applications.
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| References | |
| Additional Infomation |
JND-3229 (CAS: 2260886-64-2) is a promising next-generation EGFR inhibitor designed to overcome the C797S resistance mutation. Its potent activity against the triple mutant EGFRL858R/T790M/C797S and its ability to inhibit tumor growth in vivo make it a valuable tool for studying resistance mechanisms in NSCLC. It is a key compound for the development of new therapeutic strategies for patients with acquired resistance to EGFR TKIs.
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| Molecular Formula |
C33H41CLN8O2
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| Molecular Weight |
617.184045553207
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| Exact Mass |
616.304
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| CAS # |
2260886-64-2
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| PubChem CID |
137628688
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| Appearance |
White to light yellow solid powder
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| LogP |
5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
44
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| Complexity |
973
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C=CC=CC=1N1CC2=CN=C(NC3C=CC(=C(C)C=3)N3CCN(C)CC3)N=C2N(C1=O)C1CCC(CC1)NC(CC)=O
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| InChi Key |
WVLWGBZNXIVAKC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H41ClN8O2/c1-4-30(43)36-24-9-12-26(13-10-24)42-31-23(21-41(33(42)44)29-8-6-5-7-27(29)34)20-35-32(38-31)37-25-11-14-28(22(2)19-25)40-17-15-39(3)16-18-40/h5-8,11,14,19-20,24,26H,4,9-10,12-13,15-18,21H2,1-3H3,(H,36,43)(H,35,37,38)
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| Chemical Name |
N-[4-[3-(2-chlorophenyl)-7-[3-methyl-4-(4-methylpiperazin-1-yl)anilino]-2-oxo-4H-pyrimido[4,5-d]pyrimidin-1-yl]cyclohexyl]propanamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~12.5 mg/mL (~20.25 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.03 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 1.25 mg/mL (2.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (2.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6203 mL | 8.1014 mL | 16.2027 mL | |
| 5 mM | 0.3241 mL | 1.6203 mL | 3.2405 mL | |
| 10 mM | 0.1620 mL | 0.8101 mL | 1.6203 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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